Activation of prostaglandin EP receptors by lubiprostone in rat and human stomach and colon

• Published in: British journal of pharmacology 2008-05, Vol.154 (1), p.126-135
• Main Authors: Bassil, A K, Borman, R A, Jarvie, E M, McArthur‐Wilson, R J, Thangiah, R, Sung, E Z H, Lee, K, Sanger, G J
• Format: Article
• Language: English
• Subjects: Alprostadil - analogs & derivatives; Alprostadil - pharmacology; Animals; Biological and medical sciences; CHO Cells; ClC‐2; Colon - drug effects; Cricetinae; Cricetulus; Electric Stimulation; EP1; EP4; Filtration; gastrointestinal; Humans; In Vitro Techniques; Isoindoles - pharmacology; Lubiprostone; Male; Medical sciences; Middle Aged; Muscle, Smooth - drug effects; nausea; Pharmacology. Drug treatments; prostaglandin; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E - drug effects; Receptors, Prostaglandin E - metabolism; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP3 Subtype; Receptors, Prostaglandin E, EP4 Subtype; Research Papers; Semliki forest virus - metabolism; Stomach - drug effects; Sulfonamides - pharmacology
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.84

Background and purpose: Lubiprostone (Amitiza), a possible ClC‐2 channel opener derived from prostaglandin E1 and indicated for the treatment of constipation, increases chloride ion transport and fluid secretion into the intestinal lumen. As lubiprostone may also directly modulate gastrointestinal motility, we investigated its actions and the possible involvement of prostaglandin EP receptor activation on rat and human isolated gastrointestinal preparations. Experimental approach: Rat and human isolated preparations were mounted in tissue baths for isometric recording. The effects of lubiprostone on muscle tension and on electrically stimulated, neuronal contractions were investigated in the absence and presence of EP receptor antagonists. Key results: In rat and human stomach longitudinal muscle, lubiprostone induced a contraction (pEC50 of 7.0±0.0, n=4 and 6.4±0.2, n=3, respectively), which was inhibited by pretreatment with the EP1 receptor antagonist, EP1A 300 nM (pEC50 reduced to 6.2±0.2, n=6), but not by the EP3 or EP4 receptor antagonists (L‐798106 and GW627368X, respectively, 1 μM, P>0.05). Lubiprostone also reduced electrically stimulated, neuronal contractions in rat and human colon circular muscle preparations (pIC50 of 8.9±0.4, n=7 and 8.7±0.9, n=6, respectively), an effect mediated pre‐junctionally. This effect was reduced by the EP4 receptor antagonist (pIC50 of 6.7±1.1, n=7 and 7.7±0.4, n=6, respectively) but not by EP1 or EP3 receptor antagonists. Conclusions and implications: In rats and humans, lubiprostone contracts stomach longitudinal muscle and inhibits neuronally mediated contractions of colon circular muscle. Experiments are now needed to determine if this additional activity of lubiprostone contributes to its clinical efficacy and/or side‐effect profile.